Post-traumatic stress disorder (PTSD) is a prevalent and debilitating syndrome that occurs in some, but not all, individuals exposed to traumatic events. Acquisition of PTSD is contingent on psychological as well as genetic factors. Several lines of research suggest that the endocannabinoid system of neurotransmitters may have a role in the etiology of PTSD through effects on the neural systems involved in fear learning and motivation. We hypothesize that in trauma-exposed individuals, variants of endocannabinoid genes are associated with altered risk for PTSD. This project will investigate a system of seven major genes important for function of the endocannabinoid system. Because endocannabinoids are rapidly synthesized on demand and metabolized, functional changes within synthesizing/metabolizing enzymes or receptors may have signaling consequences. Such consequences may be reflected in risk for psychiatric illness. We will examine genes involved in the synthesis of endocannabinoids [NAPE-PLD (N-arachidonoyl phosphatidylethanolamine-hydrolyzing Phospholipase D), C11orf11 (chromosome 11 open reading frame 11 aka diacylglycerol lipase-alpha), PTPN22 (protein tyrosine phosphatase, non-receptor type 22)];response to endocannabinoids [CNR1 (cannabinoid receptor 1 aka CB1), CNR2 (cannabinoid receptor 2 aka CB2)], and degradation of endocannabinoids [FAAH (fatty acid amide hydrolase), MGLL (monoglyceride lipase)]-referred to collectively hereafter as "endocannabinoid system genes" (ESGs). We will perform this analysis in a heavily traumatized sample of over 1000 subjects (predominantly African-American) recruited from an inner-city general medical clinic. This project will test the hypothesis that polymorphisms of the ESGs are associated with differential risk for PTSD diagnosis and symptom severity.